FIVE-MEMBERED RING FORMATION 138 5 Membered Rings

HO O

CO2H CO2H

HO OH HO OH

PGF2a PGE2 Me H Me Me Me

Me Me Me Me Hirsutene Modhephane Isocumene

1. Intramolecular SN2 Reactions 2. Intramolecular Aldol Condensation and Michael Addition 3. Intramolecular Wittig Olefination 4. Ring Expansion and Contraction Reactions a. 3 ® 5 b. 4 ® 5 c. 6 ® 5 5. 1,3-Dipolar additions 6. Nazarov Cyclization 7. Arene-Olefin Photocyclization 8. Radical Cyclizations 9. Others

Synthesis 1973, 397; ACIEE 1982, 21 , 480;

Intramolecular SN2 Reaction 5-exo-tet: favored O

LDA O JCSCC 1973, 233

Br O O O CO2Me CO2Me

Br

CN CN OH JACS 1974, 96 , 5268 O FIVE-MEMBERED RING FORMATION 139 O Cl

O JACS 1979, 101 , 5081 RO2C CO R RO2C Cl 2 CO2R

O O

NaH, DMSO JCSCC 1979, 817

TsO

Intramolecular Aldol Condensation 5-exo-trig: favored intramolecular aldol condensation of 1,4-diketones

O O R R O R' R'

O O CH3 CH3 TL 1982, O 29, 2237 CH3 CH3 Br Br

O NaOMe, MeOH O JACS 1980, 102 , 4262 O CO2Me CO2Me

O O NaOH JOC 1983, O O 48 , 1217 O

Intramolecular Michael Addition 5-exo-tet: favored Organic Reactions 1995, 47, 315-552 O O JACS 1979, 101 , 7107 O MeO2C O FIVE-MEMBERED RING FORMATION 140 Intramolecular Wittig Olefination Tetrahedron 1980, 36, 1717 O O - O 1) (MeO) P(O)CH P(OMe)2 2 2 O 2) Collins O

C5H11 THPO OTHP C5H11 THPO OTHP JOC 1981, 46 , 1954 O CO2H

base

C5H11 THPO

OTHP C5H11 HO OH

Ring Expansion Reactions - 3 ® 5: Vinyl Cyclopropane Rearrangement Organic Reactions 1985, 33, 247.

O _ OTMS SPh2 O

O H O O H H O O O TMSO

JACS 1979, 101 , 1328 O H O

- 4 ® 5: Reaction of cyclobutanones with Diazomethane Me Cl Me Cl CH2N2 Me O O O TL 1980, 21 , 3059 Me Cl Me Me CH2N2 O Cl Cl Cl

Cl O O Cl Cl CH3 Cl CH2N2 CH3 O CH3 O CH3

Ph JACS 1987,109 , 4752 Ph FIVE-MEMBERED RING FORMATION 141 Ring Contraction Reactions - 6 ® 5: Favorskii Reaction Organic Reactions 1960, 11 , 261

_ O O OH -O OH CO2H Cl _

1,3-Dipolar Addition to Olefins 1,3-Dipolar Cycloaddition Chemistry , vol 1 & 2 (A. Padwa ed.) (Wiley, NY 1984); ACIEE 1977, 16 , 10. Chem Rev. 1998, 98, 863.

1,3-Dipole (4p) + LUMO _ b a c

4ps + 2ps Alkene (2p) HOMO

- trimethylenemethane (TMM) ACIEE 1986, 25 , 1. Synlett 1992, 107.

high temperature •

• TMM

CO2Me MeO2C MeO2C CO2Me H CH D 3 , MeCN • • N -N • N 2 • H JACS 1981, 103 , 2744 note: TMM usually reacts poorly w/ electron defficient olefins _ Pd(0) Me3Si OAc + PdLn

O O H O Me3Si OAc O TL 1986, 27 , 4137 Pd(0), 80°C MeO2C CO2Me

Ni(COD)2, 35 °C ACIEE 1985, 24 , 316 TL 1983, 24 , 5847 CO Me CO2Me 2

- a ,a '-dihaloketones O O OFeLn Fe(CO) Ar 9 ACR 1979, 12 , 61 + Br Br Ar FIVE-MEMBERED RING FORMATION 142 - nitrones ACR 1979, 12 , 396; Organic Reactions, 1988, 36 , 1 O - O + N N R2 R1 R1 R R2 3 R3 Nitrone

JACS 1964, O 86 , 3756 - O N N

Me N O OH O 1) MeI Me2N Me MeNHOH, Me JOC 1984, 2) H2, Pd/C EtONa 49 , 5021

H H H H H

MeO2C MeO2C NH Bn NH Bn N N O - O JACS 1983, S S 104 , 6460 C4H9 C4H9

- nitrile oxides O O - + O OH N N N O O H ArNCO 2 JACS 1992, 104 , 4023

CO Et CO Et CO2Et CO2Et 2 2

O O OH O O 1) DHP, PPTS OTHP 1) Swern Bu BOTf, iPr EtN, 2 2 CH2Cl2, •¯ 2) NH2OH•HCl N O CH2Cl2, -78°C N O 2) LAH AcONa, MeOH O CH (60%) 3 OH (89%) H Ph (99%) Ph OTHP OTHP OTHP NaOCl, H2O, + _ H , Raney Ni, H O, N 2 2 CH2Cl2 THPO O MeOH, B(OMe)3

N (88%) O N (88%) OH O OH OTHP O 1) PPTS, EtOH, •¯ O 1) TBS-Cl, DMF, HF•pyridine, 2) (CH ) C(OMe) , imidazole 3 2 2 CH CN, pyridine PPTS 3 Cassiol 2) nBuLi, THF OH TL 1996, 37, 9292 3) Swern (73%) Bu Sn 3 O (48%) O O TBSO TBSO HO OH (80%) O O O OH FIVE-MEMBERED RING FORMATION 143

OTBS OTBS OTBS LAH TL 1993, 34, 3017

N N NH + O OH 2 O _

Arene -Olefin Photocyclization Organic Photochemistry 1989, 10 , 357 - the photochemistry of benzene is dominated by the singlet state

1 * hn

*

hn * OAc OAc

*

JACS 1982, Me2CuLi O O 104 , 5805 JCSCC, 1986 247 Me

1) FVP * 2) H2, Pd/C *

hn isocume + +

*

Tetrahedron 1981,37 , 4445 *

* hn * OMe OMe JACS 1981, 103 , 688 OMe cedrane

* HO AcO hn AcO * H+

H TL 1982, 23 , 3983 TL 1983, 24 , 5325 FIVE-MEMBERED RING FORMATION 144 Intramolecular Photochemical [2+2] "Rule of Five" O O

hn

O O O O JOC 1975, 40 , 2702 JOC 1979, 44 , 1380 hn

O O Nazarov Cyclization review: Synthesis 1983, 429 Organic Reaction 1994, 45, 1 - cyclization of allyl vinyl or divinyl ketones O O

H3PO4/HCO2H

O O

H3PO4/HCO2H

- 1,4-hydroxy-acetylenes

H SO , MeOH JOC 1989, HO 2 4 OH H 54 , 3449 O H OH OH

- Silicon-Directed Nazarov O O Tetreahedron FeCl3 1986, 42 , 2821

SiMe3 Me Me

- Tin -directed Nazarov TL 1986, 27 , 5947

Radical Cyclization B. Giese Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon Press; NY) 1986; Bull. Soc. Chim. Fr. 1990, 127 , 675; Tetrahedron 1981, 37 , 3073; Tetrahedron 1987, 43, 3541; Advances in Free Radical Chemistry 1990, 1, 121. Organic Reactions 1996, 48, 301-856.

Radical Addition to multiple bonds: 1. Free radical addition is a two stage process involving an addition step followed by an atom transfer step. 2. In general, the preferred regioselectivity of the addition is in a manor to give the most stable radical (thermodynamic control) FIVE-MEMBERED RING FORMATION 145 Advantages of free radical reactions: 1. non-polar, little or no solvent effect 2. highly reactive- good for hindered or strained sysntems 3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not necessarily need to be protected Mechanism of radical chain reactions 1. initiation 2. propagation 3. termination (bad) Formation of carbon centered radicals: tin hydride reduction of alkyl, vinyl and aryl halides, alcohol derivatives: xanthates, thionocarbonate, thiocarbonylimidazolides organosselenium & boron compounds carboxylic acid derivatives (Barton esters) reduction of organomercurials thermolysis of organolead compounds thermolysis or photolysis of azoalkanes. Radical Ring Closure For irreversible ring closure reaction, the kinetic product will predominate. Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode producing the most stable radical. However, the 5-exo-trig is about 50 time faster

• •

k1,5 • k1,6

kinetically thermodynamically favored favored

•

• • 3-exo-trig + vs 100 : 0 4-endo-trig • • • + 4-exo-trig vs 100 : 0 5-endo-trig • • • + 5-exo-trig vs 98:2 6-endo-trig • • • + 6-exo-trig vs 85:15 7-endo-trig • • • 7-exo-trig + vs 8-endo-trig 100 : 0 FIVE-MEMBERED RING FORMATION 146 • • and radicals open up fast and are not synthetically useful; often used as probes for radical reaction

Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization

• • • +

48:1 • • • +

>200:1 • • • +

2:3 • • • +

< 1:100

Stereochemistry of 5-hexenyl radical cyclization 1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes 2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes

2 Bu SnH H 3 R Br • R + R H R 65 : 35 prefered transition state

R • R R R Br + 3 H H 75 : 25 H 4 + Br • R R H R 83 : 17 R

R Bu3SnH R Br • + 1 H R 73 : 27 R FIVE-MEMBERED RING FORMATION 147

Br nBuSnH, JACS 1983, AIBN 105 , 3720

OH CN OH CN

Bu3SnH, AIBN JACS 1990, 112, 5601

CO2Me Br CO2Me Br OH

H Si Si H Bu SnH O H2O2 O 3 OH

THPO THPO THPO multiple cyclizations: D. Curran Advances in Free Radical Chemistry 1990, 1, 121. OTBS O OAc 1) NaBH , CeCl 4 3 1) LDA, THF O 2) Ac2O, Et3N 2) TBSCl 70 °C O

OTBS PhSe PhSeCl, CH Cl O H2O2 O + 2 2 THPO CuSMe2 Li O O

THPO 1) PPTS, EtOH I 1) Me Si Li 2) LAH 3 (1.0 equiv) CO2H 3) (CF3SO2)2O I pyridine 2) CsF 4) Bu4NI, PhH

Me I • H Bu SnH, AIBN 3 JACS 1985, PhH, reflux 107 , 1148

H H (±)-hirsutene

O CH3MgBr, HO 1) I2 O O 2) DBU O CuBr•SMe2 O O O MgBr

CuBr•SMe2, THF O 1) LAH 2) CH SO Cl CO2Me O HO 3 2 1) CH3MgBr O 3) NaI (excess) Br 4) Li 2) Me3SiBr 5) CrO3, H2SO4, H2O

H H Bu3SnH, AIBN • PhH, reflux (±)-capnellene Tetrahedron Lett. 1985, 41, 3943 H3C H FIVE-MEMBERED RING FORMATION 148

O O Me O nBuSnH, O AIBN JACS 1986, 108, 1106 Me Me

Me Br OH CHO H JACS 1988, O O SmI2, THF 110 , 5064 O O H radical trapping OEt I O OEt OEt O nBuSnH, O tBuNC AIBN JACS 1986, 108 , 6384

RO • RO RO CN

can also be trapped with acrylate esters or acrylonitrile.

OEt OEt O OEt OEt I Me3Si nBuSnH, O C H O O O 5 11 140° AIBN SiMe Brook 3 rearrangement • C5H11 C5H11 RO RO RO O RO OTMS OEt HO Pd(OAc) , 1) (S)-BINAL-H HO 1) Wittig 2 O CHO 2) deprotect CH3CN 2) HCl, H2O, THF CO2H

C5H11 C5H11 RO HO OH (+)-PGF RO O 2a

Paulson-Khand Reaction Tetrahedron 1985, 41 , 5855; Organic Reactions 1991, 40 , 1. O O R'' R R R R' R'' Organometallics + Co2(CO)6 1982, 1 , 1560 R' R' R''

O

JOC 1992, Co2(CO)8, NMO 57 , 5277

O O O O FIVE-MEMBERED RING FORMATION 149

Ph Cp2TiCl2, EtO2C CO Et 2 EtMgBr, CO CO2Et O JOC 1992, Ph 57 , 5803 CO2Et

Ring-Closing Metathesis Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.

P(C6H11)3 Ph O Cl O O OH O Ru Bu2BOTf, Cl CH2Cl2, -78°C P(C H ) N O N O 6 11 3 CHO (97%) (82 %) Ph Ph

OH O O LiBH4, OH THF, MeOH J. Org. Chem. 1996, 61, 4192 N O OH (78%)

Ph

Diazoketones Tetrahedron 1981, 37 , 2407; Organic Reactions 1979, 26 , 361 O O N2 R1 BF3 R1 TL 1975, 4225 R 2 R2

FVP of Acetylenic Ketones O O O R1 FVP R1 R R TL 1986, 3 R1 3 27 , 19 R3 R2 H R •• 2 H R2